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Antagonizing the ghrelin receptor has potential as a therapeutic approach in the treatment of obesity and type 2 diabetes. Therefore, the aim was to pharmacologically characterize the novel small\u2010molecule antagonist PF\u201005190457 and assess translational pharmacology<jats:italic>ex vivo<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Radioligand binding in filter and scintillation proximity assay formats were used to evaluate affinity, and europium\u2010labelled GTP to assess functional activity. Rat vagal afferent firing and calcium imaging in dispersed islets were used as<jats:italic>native<\/jats:italic>tissues underlying food intake and insulin secretion respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>PF\u201005190457 was a potent and selective inverse agonist on constitutively active ghrelin receptors and acted as a competitive antagonist of ghrelin action, with a human<jats:italic>K<\/jats:italic><jats:sub>d<\/jats:sub>of 3\u00a0nM requiring 4\u00a0h to achieve equilibrium. Potency of PF\u201005190457 was similar across different species. PF\u201005190457 increased intracellular calcium within dispersed islets and increased vagal afferent firing in a concentration\u2010dependent manner with similar potency but was threefold less potent as compared with the<jats:italic>in vitro K<\/jats:italic><jats:sub>i<\/jats:sub>in recombinant overexpressing cells. The effect of PF\u201005190457 on rodent islets was comparable with glibenclamide, but glucose\u2010dependent and additive with the insulin secretagogue glucagon\u2010like peptide\u20101.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Together, these data provide the pharmacological<jats:italic>in vitro<\/jats:italic>and<jats:italic>ex vivo<\/jats:italic>characterization of the first ghrelin receptor inverse agonist, which has advanced into clinical trials to evaluate the therapeutic potential of blocking ghrelin receptors in obesity and type 2 diabetes.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.13439","type":"journal-article","created":{"date-parts":[[2016,1,19]],"date-time":"2016-01-19T20:45:10Z","timestamp":1453236310000},"page":"1452-1464","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Pharmacological characterization of the first in class clinical candidate 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